Recent evidence shows that free radicals from H2O2 and lipid peroxides stimulate prostaglandin synthesis in intact cell and microsomal preparations. Prostaglandins have been shown to decrease coronary vascular resistance following coronary artery occlusion, and to have a protective role in regional myocardial ischemia. In the isolated rabbit heart, nitroglycerin and sodium nitroprusside decrease coronary vascular resistance. In addition, they form free radicals and may stimulate lipid peroxide formation. The objectives of part 1 of this research are to determine if H2O2, nitroglycerin and sodium nitroprusside stimulate prostaglandin synthesis in the heart and to determine if the decreased coronary vascular resistance produced by these agents is, at least in part, mediated by prostaglandins. To accomplish the objectives, H2O2, nitroglycerin and sodium nitroprusside will be infused into ischemic and non-ischemic isolated rabbit hearts in the absence and presence of indomethacin and into hearts prelabeled with 14C-arachidonic acid. Changes in vascular resistance and radiolabeled prostaglandin production, as assessed by thin layer chromatography-liquid scintillation techniques, will be measured during these interventions. The results will contribute to the long-term goals of 1) facilitating a better understanding of the biochemistry of prostaglandin production in the heart during ischemia and normal O2 tension and 2) understanding the mechanism by which H2O2, nitroglycertin and nitroprusside alter coronary vascular resistance. Part II of this project will examine the possibility that digoxin stimulates prostaglandin production and that endogenous prostaglandins are important modulators of digoxin vasoactivity. To accomplish this objective, digoxin will be administered to rabbits and to isolated rabbit hearts in the absence and presene of non-sterioidal anti-inflammatory agents or hydrocortisone and to isolated hearts prelabeled with 14C arachidonic-acid. Changes in vascular resistance and prostaglandin production will be assessed. These results will contribute to the long term goal of defining the importance of endogenous prostaglandins for the modulation of pharmacologic activity of vasoactive drugs. In addition, these results may elucidate a clinically important interaction between inhibitors of prostaglandin synthesis and digoxin.